EPITHELIOID SARCOMA. Cyril Fisher MD DSc FRCPath London, England

Transcription

1 1 EPITHELIOID SARCOMA Cyril Fisher MD DSc FRCPath London, England Introduction Epithelioid sarcoma is a tumor of mesenchymal cells displaying differentiation that is multidirectional but predominantly epithelial. Soft tissue tumors composed of large polygonal cells resembling carcinomas were observed from time to time under a variety of names in the early literature on synovial sarcoma 1 or giant cell sarcomas. In 1961, Laskowski reported examples of aponeurotic sarcoma in an account which was published first in Polish 2 and republished in English a decade later. 3 Enzinger, while noting the prior accounts, then described 62 cases in 1970 as epithelioid sarcoma, 4 the term which has been used ever since. Chase and Enzinger followed this 15 years later with a definitive study of 241 cases which emphasized the behavior and assessed in detail the prognostic factors for 202 cases of this rare sarcoma. 5 The usual-type epithelioid sarcomas, located most commonly in the distal extremities, have cells with only mild atypia, although they can appear more pleomorphic in recurrences or metastases. A group of more proximally- or axially-located tumors which are pleomorphic and aggressive from the outset have been termed proximal-type (aggressive, large cell) epithelioid sarcoma. Over 70 examples of this variant have now been reported; their existence as a subset was acknowledged in (but excluded from) the AFIP s 1985 series of 241 epithelioid sarcomas. 5 Clinical features Epithelioid sarcoma occurs at any age with a peak in young adults and more frequently in males. A higher than usual proportion of cases (up to 20% 5-27% 6 ) have been associated with antecedent trauma, including origin in scar tissue 7, 8 although any causal relationship is obviously speculative. A majority of cases occur in the extremities, especially the arm and hand, as a subcutaneous or more deeply located nodule which grows slowly and can ulcerate. The ulcers have raised margins and are non-healing and clinically can resemble granuloma annulare. Deeper lesions can extend along tendon sheaths or aponeuroses. cases 60 Epithelioid sarcoma: Age and Sex Male Female age years Data from Chase and Enzinger, 1985

2 2 The proximal variant occurs in adults (range 13 to 80 years, median 40 years), with a slight predominance in males, and mainly in proximal or axial regions including limb girdles, pelvis, perineum or genital tract, mediastinum and trunk The usual presentation is with symptoms of an infiltrative mass in deep soft tissue, and less frequently in skin or subcutis, which can attain a large size, up to 20cm in diameter, and which commonly displays hemorrhage and necrosis. Microscopic features Enzinger s original paper described comprehensively the features of this tumor, including some variations which have since been expanded as subtypes. The tumor forms nodules with central necrosis, and ulceration in cutaneous examples, composed of relatively uniform polygonal cells, often with loss of cohesion, which merge peripherally into spindle cells without demarcation. The cells have minimal pleomorphism but occasional mitoses and relatively abundant deeply eosinophilic cytoplasm. Stromal changes include hemorrhage into spaces (subsequently noted as the angiomatoidp 12, 13 or angiosarcoma-like variant), desmoplasia with cords of bland spindle cells sometimes with storiform pattern (the fibroma-like variant 12, 14 with an affinity for involving bone), and focal calcification or metaplastic ossification in some cases. The larger 1985 series excluded pleomorphic examples, added new observations and quantitated the occurrence of some of the features: intracytoplasmic vacuoles, multinucleated giant cells (5%), storiform pattern (5%), calcification (19%), osseous metaplasia (10%), chondroid metaplasia (1 case), lymphocytic reaction, vascular invasion (11%), and neural invasion (7%). In the proximal variant, there is a multinodular pattern of large polygonal cells with vesicular pleomorphic nuclei and prominent nucleoli. There is often rhabdoid cytomorphology, which can be focal or predominant. Sometimes there is a signet-ringlike vacuolation, or a minor spindle cell component but this is less common than in usualtype epithelioid sarcoma. The nodules frequently have central necrosis, with or without a geographic pattern, as in usual epithelioid sarcoma, and a pseudoangiomatous architecture is occasionally seen. Rarely, a tumor has features of both variants. It should also be noted that the usual and proximal types can each occur in either proximal or distal locations. Immunohistochemical findings Cytokeratin positivity in epithelioid sarcoma was observed by Chase et al in and in the subsequent 1985 AFIP series 75% of cases were found to be CK positive. Also, 38% of cases expressed CEA, and 53% alpha-1 antitrypsin, but these markers are no longer used routinely in this context. It has since been amply confirmed that virtually all cases are positive for cytokeratin and for EMA (usually with membranous staining). Most cases co-express vimentin as well as cytokeratin, but a few are vimentin-negative. 16 SMA and neurofilament are also detectable, especially in the spindle cells. CD34 is positive in over half of epithelioid sarcomas unlike in carcinoma which is almost always CD34-negative. Two large studies from AFIP have further defined the immunophenotype of epithelioid sarcoma, which expresses cytokeratins 8 (94%), CK14 (48%) and CK19 (72%), but 12, 17 rarely CK7 (22%), CK20 (15%) or CK5/6 (30%, focal). No single marker was able to distinguish the main 4 histologic subtypes of epithelioid sarcoma. Desmin was positive in several cases in one study 9 but negative in all variants of epithelioid sarcoma examined in a larger series. 12 An important negative is S100 protein although HMB45 was found in a minority of cells in 3 cases of proximal epithelioid sarcoma. 9 Hasegawa

3 3 et al found positivity in the proximal variant for EMA in 85%, CD34 in 45%, CD99 in 25% and desmin or SMA in 15%. 10 These 12, 18 and other 19 findings are depicted below: % Epithelioid Sarcoma: Immunohistochemistry 0 Vim EMA K8 K ß K5/6 K7 K20 CD34 Act Des CD117 ß-cat S100pr Ultrastructural findings Electron microscopy reveals a spectrum of appearances from undifferentiated cells to carcinoma-like epithelial differentiation. 20 Enzinger originally described cells with filopodia, junctions and intermediate filaments. Subsequent accounts have confirmed these observations and extended them to include desmosomes, surface microprocesses, and interdigitating cell membranes indicating epithelial (sometimes interpreted as synovial sarcoma-like) differentiation. In addition, cells with dilated rough endoplasmic reticulum and peripheral myofilament bundles, the latter especially seen in spindle cells at the periphery of the nodules, have been observed, resembling fibrohistiocytic, fibroblastic or myofibroblastic differentiation and mimicking the appearances seen in pleomorphic sarcomas of MFH type or pleomorphic myofibrosarcoma. 21 The rhabdoid cells contain abundant cytoplasmic whorls of intermediate filaments. Genetic findings There are no consistent or specific findings. Some tumors are diploid 22 and others polyploid. 23 Abnormalities involving 18q11 and 22q11 (including 22q deletions) have been observed. 24, 25 Chromosomal rearrangements t(8;22)(q22;q11) in usual-type epithelioid sarcoma 26 and t(10;22) in two cases of proximal epithelioid sarcoma 27 have been described. In addition, inactivation of a tumor suppressor gene SMARCB1/INI1 located at 22q11 has been found in proximal but not usual-type epithelioid sarcoma. 28 The 22q region, which carries the locus of the NF2 tumor suppressor gene is also affected in neurofibromatosis type 2, in association with which one example of usual-type epithelioid sarcoma has been reported. 29 Differentiation The morphologic observations have been the basis of several hypotheses about the lineage or nature of epithelioid sarcoma. Enzinger considered but rejected epithelioid sarcoma as a variant of synovial sarcoma. He suggested that epithelioid sarcoma was a mesenchymal tumor differentiating along fibroblastic or histiocytic lines, and noted the resemblance to cells of epithelioid granuloma. Later observers emphasized histiocytic, 7, 30 fibroblastic 31 or myofibroblastic 20, 32 differentiation, and the discovery of epithelial marker positivity was used as additional support for a relationship with 7, 33, 34 synovial sarcoma which some had postulated based on ultrastructure. The possibilities of endothelial 35 and perineurial 36 differentiation have also been raised. In truth, because of the multidirectional differentiation and the variation in features from case to case, all these suggestions except synovial sarcoma might be appropriate.

4 4 Notwithstanding its epithelial differentiation, epithelioid sarcoma differs from synovial sarcoma in many respects. Clinically, epithelioid sarcoma is often dermal and presents in the finger or hand, features which would be exceptional for synovial sarcoma. Epithelioid sarcoma is not truly biphasic but the spindle cells emerge at the edge of the tumor nodules with continuous transition from the polygonal cells. There is no glandular formation, morphologically or ultrastructurally, and no external lamina. Synovial sarcomas display epithelial markers more focally, express CK7, which is usually absent from epithelioid sarcoma 12, 37 and are almost always CD34-negative. 38 Genetically, the t(x;18) with SYT-SSX fusion genes which is characteristic of synovial sarcoma 39 is never found in epithelioid sarcoma which has variable abnormalities including most commonly those of the 22q region. In the current WHO classification, epithelioid sarcoma is categorized as a tumor of uncertain differentiation and described as being of unknown lineage. 40 Behavior Epithelioid sarcoma recurs persistently, often with successive lesions appearing more proximally, and eventually metastasizes. Of Enzinger s original cases, 87% recurred (increasing to 93% of those with longer than 5 years follow up), and 30% metastasized. With a mean follow up period of 7 years, 20% died of disease. In the large series of Chase and Enzinger, of 202 cases with follow-up 77% recurred, and 45% metastasized predominantly to lungs (51%), local lymph nodes (34%), scalp (22%) (especially in males) and other skin areas, bone, brain, liver and pleura. Adverse prognostic factors include proximal location (71% metastasized vs. 38% of distal cases), amount of necrosis and vascular invasion, and inadequate excision. Favorable factors are young age at first diagnosis, female sex (78% 5-80% 41 survival rate vs. 40% 41-64% 5 for males), and small size (<2cm). Spillane et al 42 found a five year survival of 70% and a 10 year survival of 42%, in a series with a metastatic rate of 40%. Because of the relatively indolent behavior, the incidence of late recurrence, and the continuing death rate, long term follow up is indicated. 5 Proximal epithelioid sarcoma is an aggressive neoplasm. In the series of Guillou et al, 9 six of 14 patients with up to 8 years follow up developed metastases, and five died of tumor. However, six patients were alive and well at last follow up including one with local recurrence at 2 months who was disease free at 8 years. In a second series of 20 cases, 65% developed local recurrence and 75% metastases, with 65% dead of disease. 10 Differential diagnosis Epithelioid sarcoma has a wide range of appearances and immunophenotype and, as noted in the title of Enzinger s original paper, it can resemble a number of non-neoplastic lesions as well as benign and malignant neoplasms. Among the most common benign diagnoses suggested by pathologists referring cases to the AFIP were fibrous histiocytoma, nodular fasciitis and other reactive proliferations, fibromatosis and giant cell tumor of tendon sheath. 5 Apart from their discriminating morphologic features, all of these, however, lack cytokeratin and EMA. The bland cytology of epithelioid sarcoma can lead to misinterpretation as granuloma annulare or other necrotizing granuloma. 43 The presence of mitotic activity, however, should raise the index of suspicion and epithelial marker positivity indicates the correct diagnosis. Carcinomas, both primary (including those of adnexal origin) and metastatic, can have a similar presentation. Immunohistochemistry can be helpful in diagnosis since CK5/6 18, 44 and p63 18 are more commonly expressed in carcinomas than in epithelioid sarcoma Furthermore, carcinomas are nearly always CD34 negative, 45 and this marker, though only expressed in about half of the cases, is particularly useful for the deep-seated

5 5 proximal variant of ES which can be misdiagnosed as metastatic carcinoma of unknown primary site. Melanoma with rhabdoid features can acquire cytokeratin and even desmin expression. 46 The diagnosis is even more confusing since such melanomas can lack S100 protein and HMB45. Thus, it might not be possible to distinguish S100 protein negative rhabdoid melanoma from proximal epithelioid sarcoma, especially as some of the latter have been reported to be HMB45 positive. 9 Clear cell sarcoma can rarely express cytokeratin 47 but is almost always positive for S100 protein and HMB45. Rhabdomyosarcoma is readily excluded by immunohistochemistry showing positive epithelial markers and absence of desmin, myogenin and MyoD1 as well as by the clinical picture. Synovial sarcoma can have plump epithelioid and even rhabdoid cells on occasion. However, it is rarely located superficially and when biphasic has discrete spindle and epithelial components. The immunoprofile of the two tumors can overlap but synovial sarcoma is often S100 protein-positive and only very rarely CD34 positive. Finally, the specific t(x;18) of synovial sarcoma is not found in epithelioid sarcomas. Epithelioid vascular tumors can resemble epithelioid sarcoma, and additionally some express cytokeratins. Epithelioid hemangioendothelioma, which can occur in skin and soft tissues and has eosinophilic cells in cords and nests in a fibromyxoid stroma, can resemble the fibroma-like variant of epithelioid sarcoma. Many of the cells, however, have vacuoles (some with a thin septum traversing the vacuole) and in addition to the other markers react for CD31 and FVIIIRAg. The recently described epithelioid sarcoma-like hemangioendothelioma, 48 which is cytokeratin-positive, differs from epithelioid sarcoma in being positive for CD31 but not CD34, and in its indolent behavior. Distinction of epithelioid sarcoma from epithelioid angiosarcoma is aided by lack of hemorrhage or significant pleomorphism, and of CD31 and FVIIIRAg. Many tumors formerly diagnosed as malignant rhabdoid tumor are now classified as proximal epithelioid sarcoma. Malignant rhabdoid tumor, composed predominantly of rhabdoid cells, occurs principally in infancy or childhood, and was recognized first in the kidney and central nervous system, and later also in various soft tissue sites. 49 Extrarenal malignant rhabdoid tumor, however, is more difficult to define because rhabdoid cells are found in varying proportions in a number of other, more specific tumor types. These include epithelioid sarcoma, melanoma, rhabdomyosarcoma and carcinoma, and some examples of poorly differentiated synovial sarcoma, extraskeletal myxoid chondrosarcoma, desmoplastic small round cell tumor, peripheral primitive neuroectodermal tumor, epithelioid malignant peripheral nerve sheath tumor, mesothelioma, and endometrial stromal sarcoma. It seems, therefore, that many if not most examples of MRT can be classified as other tumors and that, like malignant fibrous histiocytoma and hemangiopericytoma, it is predominantly a pattern and only rarely an 50, 51 entity which is essentially a diagnosis of exclusion. Conclusion Enzinger s original descriptions represent the definitive accounts of epithelioid sarcoma, encompassing its clinical, morphologic and behavioral features. 35 years after Enzinger s first report, epithelioid sarcoma, a mesenchymal tumor with coexistent epithelial differentiation, is still of uncertain nature (i.e. without a normal counterpart cell), and without a conclusive genetic basis. It remains, however, a distinct entity with characteristic appearances, ultrastructure and immunophenotype.

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